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Principal Investigator: CRAIG P HERSH
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $675,739
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Multiple lines of evidence point to the role of adaptive immunity as response to viral infections and/or as
misdirected autoimmune response in subjects with COPD and emphysema. There is support for an association
between adaptive immune responses and COPD progression, but a direct link has not been made. In this
proposal, we will utilize blood samples from 3,000 well-characterized subjects from the COPDGene Study, which
include longitudinal follow-up and extensive available omics datasets. We will employ state of the art Phage
ImmunoPrecipitation Sequencing (PhIP-Seq) technology to efficiently and comprehensively assess samples for
autoantibodies and antibodies indicative of prior viral infections. Our first hypothesis is that previous infections with
respiratory viruses, or differential immune responses to viral infections, are associated with more rapid
progression of COPD, specifically lung function decline. The second hypothesis is that autoantibodies are
associated with COPD, emphysema, and more rapid lung function decline. Aim 1: Human Virome and Lung
Function Decline. We will test for associations between baseline viral antibodies and longitudinal decline in lung
function at the 5 and 10-year study visits. We will also measure antiviral antibodies at the 5-year visit and test for
lung function decline over the subsequent 5 years in subjects who acquire new or higher levels of specific viral
antibodies, signifying interval infections. We will test whether these effects are modified by host factors including
sex and HLA genotypes. Aim 2: Autoimmunity and COPD Outcomes. We will use PhIP-Seq to identify the
presence of autoantibodies, we and will test for association between autoantibodies and COPD status, lung
function decline, and quantitative emphysema parameters from chest CT scans. We will measure autoantibodies
at the 5-year visit and test for lung function decline over the subsequent 5 years in subjects who acquire new or
higher levels of autoantibodies. We will again test whether these effects are modified by host factors including sex
and HLA genotypes. Aim 3: Adaptive Immunity and Chronic Inflammation Using whole blood RNA-
sequencing data from the year 5 visit, we will derive gene expression scores representing antiviral and
inflammatory pathways. We will test the association of these gene expression scores with viral antibodies and
autoantibodies to discover novel drivers of persistent inflammation. We will validate the association of
inflammatory gene expression scores with lung function and CT emphysema in a larger sample of COPDGene
subjects with RNA-sequencing data. This proposal will complement the existing clinical, genetic and
transcriptomic data in COPDGene by incorporating viral exposures and autoantibodies into longitudinal models
of COPD progression. To accomplish this research, we have assembled a multidisciplinary team with expertise
in in PhIP-Seq, COPD phenotyping, molecular immunology, genetic epidemiology, biostatistics and
bioinformatics.
Terms: <Acceleration><Active Follow-up><Acute><Airway Disease><Antibodies><Assay><Autoantibodies><Autoimmune Diseases><Autoimmune Responses><Autoimmune Status><Autoimmunity><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Biometrics><Biometry><Biostatistics><Blood Plasma><Blood Sample><Blood specimen><CAT scan><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COPD><CT Lung Screening><CT X Ray><CT Xray><CT imaging><CT scan><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Clinical><Complement><Complement Proteins><Computational Biology><Computed Tomography><Coughing><Data><Data Set><Development><Disease><Disease Outcome><Disease Progression><Disorder><Emphysema><Epidemiology><Female><Gene Expression><Genes><Genetic><Genotype><HL-A Antigens><HLA Antigens><Host Factor><Host Factor Protein><Human Leukocyte Antigens><IFN><Immune><Immune response><Immunes><Immunological response><Infection><Inflammation><Inflammatory><Integration Host Factors><Interferons><Lead><Leukocyte Antigens><Link><Lung CAT Scan><Lung CT><Lung CT scan><Lung Function Tests><Lymphoid Follicle><Measures><Modeling><Molecular Immunology><Molecular Mimicry><Morbidity><Morbidity - disease rate><Mucous body substance><Mucus><Pathway interactions><Pb element><PhIP-seq><Phage ImmunoPrecipitation Sequencing><Plasma><Plasma Serum><Predisposition><Prevention><Production><Pulmonary Emphysema><Pulmonary function tests><RNA Seq><RNA sequencing><RNAseq><Research><Respiratory Epithelium><Reticuloendothelial System, Serum, Plasma><Risk Factors><Role><Sample Size><Sampling><Severity of illness><Shortness of Breath><Structure of respiratory epithelium><Susceptibility><Symptoms><T8 Cells><T8 Lymphocytes><Technology><Testing><Tomodensitometry><Variant><Variation><Viral><Viral Antibodies><Viral Diseases><Virus><Virus Diseases><Visit><Whole Blood><Woman><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><accept vaccination><accept vaccine><active followup><adaptive immune response><adaptive immunity><airway epithelium><anti-viral antibody><autoimmune antibody><autoimmune condition><autoimmune disorder><autoimmune reactivity><autoimmunity disease><autoreactive antibody><autoreactivity><catscan><chest CT><chest computed tomography><chronic obstructive pulmonary disorder><clinical phenotype><complementation><computed axial tomography><computer biology><computer tomography><computerized axial tomography><computerized tomography><computerized tomography lung screening><develop a vaccine><develop vaccines><development of a vaccine><developmental><disease phenotype><disease severity><driving><emphysematous><epidemiologic><epidemiological><follow up><follow-up><followed up><followup><genetic epidemiologic study><genetic epidemiology><genomic data><genomic data-set><genomic dataset><heavy metal Pb><heavy metal lead><host response><human virome><immune system response><immunoresponse><improved><lung computerized axial tomography scan><lung computerized tomography><lung computerized tomography scan><lung function><lung function decline><mortality><mucous><multidisciplinary><new approaches><non-contrast CT><noncontrast CT><noncontrast computed tomography><novel><novel approaches><novel strategies><novel strategy><pathway><peripheral blood><pulmonary function><pulmonary function decline><respiratory><respiratory tract epithelium><respiratory virus><response><self reactive antibody><sex><social role><transcriptome sequencing><transcriptomic sequencing><transcriptomics><vaccination acceptability><vaccination acceptance><vaccination confidence><vaccination uptake><vaccination willingness><vaccine acceptability><vaccine acceptance><vaccine confidence><vaccine development><vaccine uptake><vaccine willingness><viral infection><virus infection><virus-induced disease>